MicroRNAs are a new paradigm in gene expression and function in complex fundamental processes such as spatial/temporal patterning during development, cell-cell and cell-organ communication, cellular and systemic regulation of metabolism, response to external stimuli and stress, and immune activation. MicroRNAs are modulated during infection with certain pathogens, such as viruses and bacteria, yet the dynamic mechanistic processes remain elusive. Plasmodium spp are intracellular parasites in the phylum Apicomplexa. Parasites in this phylum actively modulate host processes, such as gene expression and immune activation, via the secretion of effector molecules. Such an active mechanism has yet to be described in infected hepatocytes with Plasmodium parasites; however, work performed in our laboratory has established that infection with malaria parasites induces an alteration in host gene expression. We hypothesize that Plasmodium parasites hijack microRNA function and expression to promote a successful infection. We propose an interdisciplinary approach to study host hepatocyte microRNA as a language for host-parasite communication, from the cell to organ and organism level. To this end, we will combine tissue-engineering with expertise in molecular and cellular biology of host-Plasmodium interactions. In this study we will use a novel co-culture primary hepatocyte infection system to carry out genome wide expression analysis via RNAseq of infected livers, high-throughput qPCR analysis of infected versus non-infected hepatocytes, and functional screens using antisense oligos to identify microRNAs in Plasmodium liver stage development. Alternatively, as a second approach we will analyze the regulation and requirement of the microRNA machinery during Plasmodium infection of hepatocytes. These two complementary approaches will provide insight into the importance of microRNA function and expression for Plasmodium infection. This interdisciplinary project aims to open up novel horizons in fundamental processes of complex multi-dimensional and multi-component interactions between the infected hepatocyte, the parasite, and their mutual environment via the action of microRNA.